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Glycolipids from the cell wall of Gram-positive bacteria have been the topic of my PhD. It is well known that many bacterial glycolipids (e.g. LPS, TDMs and PIMs) have profound immunological effects, and therefore the characterisation, biological testing and synthesis of gram-positive bacterial glycolipids is of interest. The first part of this thesis includes a description of the extraction and characterisation of glycolipids from gut bacteria including Bifidobacterium and Lactobacillus genus and the second part focussed on the chemical synthesis of Streptococcus sp. DSM 8747 glycolipids and lipoteichoic acid analogues (LTA).  Members of the genus Lactobacillus are common in the gut microbiota and are often used as probiotics. As lactobacilli are known to have benefits to human health, compounds on its surface are of high interest. To date, the structures of the glycolipids from L. plantarum have not been conclusively assigned. Thus, for the first time, the full characterisation of the four principal glycolipids of the L. plantarum cell wall was reported using sugar, linkage and FAME analysis, as well as ESI-MS/MS and 1D- and 2D-NMR spectroscopy. The major glycolipids were identified as: α-D-Glcp-diglyceride, α-D-Galp-(1→2)-α-D-Glcp-diglyceride, β-D-Glcp-(1→6)-α-D-Galp-(1→2)-6-O-acyl-α-D-Glcp-diglyceride and β-D-Glcp-(1→6)-α-D-Galp-(1→2)-α-D-Glcp-diglyceride. These glycolipids showed weak activation of murine bone marrow macrophages in an initial biological screen.  After having identified the structures of the glycolipids from L. plantarum, the glycolipids from Bifidobacterium, a dominant member of the gut microbiota in infants, were extracted. Bifidobacteria are considered to be important in the development of a healthy immune system and they are believed to exhibit anticancerous properties, alleviate the symptoms of irritable bowel syndrome, and are thought to reduce atopic disease. Despite this, the chemical nature of immunomodulatory compounds on the surface of bifidobacteria has not been well documented. Thus, glycolipids were extracted from B. longum subsp. infantis, fractionated chromatographically and analyzed using NMR spectroscopy, constituent sugar and linkage analysis, and fatty acid analysis. These analyzes revealed a novel glycolipid, containing an unprecedented mixed acetal moiety and a galactofuranose moiety as a head group. However, like L. plantarum glycolipids, bifidobacterial glycolipids were shown only to induce little macrophage activity when tested.  Having successfully characterised a novel glycolipid present in bifidobacteria, analogues of this glycolipid as well as poly(glycerophosphate) lipotechoic acids analogues (LTAs) were then synthesised. Much debate still remains about the role of LTAs during Gram-positive bacterial infection. This is partly due to differences in the biological activities of extracted versus synthesised LTAs and highlights the need for structurally defined non-contaminated LTAs when investigating the effect of these glycolipids on the innate immune response. An efficient synthesis of the core lipoteichoic acid (LTA) anchor of the Streptococcus species DSM 8747, and derivatives thereof, was achieved. These Streptococcus glycolipids contain a galactofuranose moiety and thus have similarities to the novel glycolipid that was found in bifidobacteria. The syntheses, which commence with readily available D-galactose, are short (7-9 steps), convergent, and high-yielding (33-37% overall yield). In total 11 different targets were synthesised. The biological activity of these compounds was also investigated, with several analogues (particularly the sn-1,2-di-acylglycerol LTA anchors) found to induce macrophage activation.

Purification, Characterisation and Synthesis of Glycerolipids Extracted from L. plantarum and B. longum subsp. infantis